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J Lipid Res. 2018 Apr;59(4):625-634. doi: 10.1194/jlr.M082040. Epub 2018 Feb 5.

Low ketolytic enzyme levels in tumors predict ketogenic diet responses in cancer cell lines in vitro and in vivo.

Author information

1
Department of Endocrinology, Huai'an Hospital Affiliated to Xuzhou Medical University, and Huai'an Second People's Hospital, Huai'an 223002, Jiangsu, China.
2
Department of Biochemistry and Molecular Biology, The College of Basic Medical Sciences, The Second Military Medical University, Shanghai 200433, China.
3
Department of Gastrointestinal Surgery/Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China.
4
Department of Hyperbaric Oxygen Therapy, The First Affiliated Hospital of The Second Military Medical University, Changhai Hospital, Shanghai 200433, China.
5
National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
6
Department of Gastrointestinal Surgery/Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China; miaomy@163.com hayuweinan@163.com shihp@vip.163.com.
7
Department of Endocrinology, Huai'an Hospital Affiliated to Xuzhou Medical University, and Huai'an Second People's Hospital, Huai'an 223002, Jiangsu, China miaomy@163.com hayuweinan@163.com shihp@vip.163.com.
8
Department of Biochemistry and Molecular Biology, The College of Basic Medical Sciences, The Second Military Medical University, Shanghai 200433, China miaomy@163.com hayuweinan@163.com shihp@vip.163.com.

Erratum in

Abstract

The ketogenic diet (KD) is a high-fat, very-low-carbohydrate diet that triggers a fasting state by decreasing glucose and increasing ketone bodies, such as β-hydroxybutyrate (βHB). In experimental models and clinical trials, the KD has shown anti-tumor effects, possibly by reducing energy supplies to cells, which damage the tumor microenvironment and inhibit tumor growth. Here, we determined expression levels of genes encoding the ketolytic enzymes 3-hydroxybutyrate dehydrogenase 1 (BDH1) and succinyl-CoA: 3-oxoacid CoA transferase 1 (OXCT1) in 33 human cancer cell lines. We then selected two representative lines, HeLa and PANC-1, for in vivo examination of KD sensitivity in tumors with high or low expression, respectively, of these two enzymes. In mice with HeLa xenografts, the KD increased tumor growth and mouse survival decreased, possibly because these tumors actively consumed ketone bodies as an energy source. Conversely, the KD significantly inhibited growth of PANC-1 xenograft tumors. βHB added to each cell culture significantly increased proliferation of HeLa cells, but not PANCI-1 cells. Downregulation of both BDH1 and OXCT1 rendered HeLa cells sensitive to the KD in vitro and in vivo. Tumors with low ketolytic enzyme expression may be unable to metabolize ketone bodies, thus predicting a better response to KD therapy.

KEYWORDS:

BDH1; HeLa; OXCT1; PANC-1; cancer; ketogenic diet; ketone bodies; metabolism; xenograft

PMID:
29414764
PMCID:
PMC5880499
DOI:
10.1194/jlr.M082040
[Indexed for MEDLINE]
Free PMC Article

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